Chapter 4 of 4
Summary
Summary & key points
- Repairing the cornea means a constant dialogue between epithelium and stroma, shaped by the tears and immune cells.
- As long as this balance holds, the cornea keeps its clarity and refractive power — the ultimate goal of any healing.
- The epithelial basement membrane is the true switch: its regeneration ends the TGF-β/PDGF inflow and hence fibrosis.
- An epithelial wound closed within a few days heals without a trace; if it lingers, it slips into delayed healing, fibrosis or melting.
- EMMPRIN/CD147 is a hub: it induces MMPs (stromal melting) and regulates the epithelial barrier via occludin (dry eye) — a therapeutic target.
- Neovascularization betrays a breach of the angiogenic (and lymphangiogenic) privilege, costing transparency and transplant immunity.
- Removing aggravating factors early — toxic drops, dryness, exposure, loss of sensation — remains the highest-yield step.
Take-home
The time to re-epithelialization and the state of the basement membrane determine the outcome: rapid closure shuts the growth-factor window and allows transparent repair; delay directs healing toward fibrosis, melting or neovascularization.
Summary table
| Parameter | Regenerative healing | Pathological healing |
|---|---|---|
| Re-epithelialization | Fast (< ~8 d) favourable | Delayed / PED (> 1 wk) at risk |
| Epithelial basement membrane | Reforms then matures (~6 wk) | Immature / persistently absent |
| Barrier (occludin) | Tight junctions intact | Occludin cleavage (EMMPRIN↑, MMP-9↑) |
| Keratocytes → myofibroblasts | Progenitor apoptosis before maturity | Persistent mature myofibroblasts (α-SMA) |
| Stromal matrix | Reorganized, ordered | Disorganized (collagen III, tenascin, GAG) |
| MMP / TIMP balance | Controlled balanced | Collagenolysis (CD147↑, TIMP↓) unbalanced |
| Vessels | Avascular cornea (privilege kept) | Neovascularization (hem- & lymph-) |
| Transparency | Preserved | Haze / opacity, loss of immune privilege |
Synthetic teaching landmarks; time thresholds are indicative and depend on the background.
References & further reading
Original teaching synthesis. The detailed reference text appears in the chapter “Cicatrisation cornéenne” (M. Cavaillé, C. Tolosa Leal, É. Gabison), in La Cornée en 3D: dégénérescences, dystrophies et déformations, Elsevier Masson, 2025.
Team's own work
- Gabison EE, Mourah S, Steinfels E, et al. (Menashi S). Differential expression of EMMPRIN (CD147) in normal and ulcerated corneas: role in epithelio-stromal interactions and MMP induction. Am J Pathol 2005;166(1):209–19. link.
- Gabison EE, Huet E, Baudouin C, Menashi S. Direct epithelial–stromal interaction in corneal wound healing: role of EMMPRIN/CD147 in MMPs induction and beyond. Prog Retin Eye Res 2009;28(1):19–33. link.
- Huet E, Vallée B, Delbé J, et al. (Gabison EE). EMMPRIN modulates epithelial barrier function through a MMP-mediated occludin cleavage: implications in dry eye disease. Am J Pathol 2011;179(3):1278–86. link.
- Catanese M, Popovici C, Proust H, et al. (Gabison EE). FISH on corneal impression cytology specimens (CICS): study of epithelial cell survival after keratoplasty. Invest Ophthalmol Vis Sci 2011;52(3):1009–13. link.
- Chang JH, Gabison EE, Kato T, Azar DT. Corneal neovascularization. Curr Opin Ophthalmol 2001;12(4):242–249. link.
- Gabison E, … Azar DT. Anti-angiogenic role of angiostatin during corneal wound healing. Exp Eye Res 2004;78(3):579–589. link.
Key literature
- Ljubimov AV, Saghizadeh M. Progress in corneal wound healing. Prog Retin Eye Res 2015;49:17–45.
- Wilson SE. Corneal wound healing. Exp Eye Res 2020;197:108089.
- Wilson SE, Torricelli AAM, Marino GK. Corneal epithelial basement membrane: structure, function and regeneration. Exp Eye Res 2020;194:108002.
- Kamil S, Mohan RR. Corneal stromal wound healing: major regulators and therapeutic targets. Ocul Surf 2021;19:290–306.
- Fini ME. Keratocyte and fibroblast phenotypes in the repairing cornea. Prog Retin Eye Res 1999;18:529–51.
- Wilson SE, Chaurasia SS, Medeiros FW. Apoptosis in the corneal wound healing response. Exp Eye Res 2007;85:305–11.
- Azar DT. Corneal angiogenic privilege: angiogenic and antiangiogenic factors in corneal avascularity, vasculogenesis, and wound healing. Trans Am Ophthalmol Soc 2006;104:264–302.
- Ambati BK, Nozaki M, Singh N, et al. Corneal avascularity is due to soluble VEGF receptor-1. Nature 2006;443:993–7.
- Cursiefen C, Chen L, Dana MR, Streilein JW. Corneal lymphangiogenesis: evidence, mechanisms and implications for transplant immunology. Cornea 2003;22:273–81.
- Dua HS, Gomes JA, Singh A. Corneal epithelial wound healing. Br J Ophthalmol 1994;78:401–8.
- Han KY, Tran JA, Chang JH, et al. Corneal epithelial cell-derived exosomes in wound healing and neovascularization. Sci Rep 2017;7:40548.
- Mannis MJ, Holland EJ (eds). Cornea, 5th ed. Elsevier, 2021.
- Wilson SE. Analysis of keratocyte apoptosis, keratocyte proliferation and myofibroblast transformation after PRK and LASIK. Trans Am Ophthalmol Soc 2002;100:411–33.
- Wilson SE. Biology of keratorefractive surgery — PRK, PTK, LASIK, SMILE, inlays and other refractive procedures. Exp Eye Res 2020;198:108136.
- Dawson DW, Volpert OV, Gillis P, et al. Pigment epithelium‑derived factor: a potent inhibitor of angiogenesis. Science 1999;285(5425):245–248.
- Kubo H, Cao R, Brakenhielm E, et al. Blockade of VEGFR‑3 signaling inhibits FGF‑2‑induced lymphangiogenesis in mouse cornea. Proc Natl Acad Sci USA 2002;99(13):8868–8873.
- Makino Y, Cao R, Svensson K, et al. Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 2001;414(6863):550–554.
Glossary of abbreviations used in this course
Scientific abbreviations and acronyms used throughout the 10 pages of this course, listed alphabetically.
No matching term.
- 95% CI
- 95% confidence interval
- AAV
- adeno-associated virus (gene-therapy viral vector)
- ABCG2
- ABCG2 transporter, a limbal stem-cell marker
- AMT
- amniotic membrane transplantation
- anti-VEGF
- anti-angiogenic treatment targeting VEGF
- ASC
- inflammasome adaptor protein (Apoptosis-associated Speck-like protein containing a CARD)
- BrdU
- bromodeoxyuridine, a cell-proliferation marker
- CCL2
- CCL2 chemokine, synonym of MCP-1; recruits circulating monocytes
- CCR2
- receptor for CCL2; marker of newly recruited monocytes/macrophages
- CD147
- cluster of differentiation 147; synonym of EMMPRIN and basigin
- CD163
- M2 macrophage marker; scavenger receptor for haemoglobin-haptoglobin
- CD206
- mannose receptor; marker of M2 polarization
- CD74
- cell-surface receptor for MIF
- CDVA
- corrected distance visual acuity
- CGRP
- calcitonin gene-related peptide
- CTGF
- connective tissue growth factor
- CX3CL1
- fractalkine, a chemokine involved in monocyte/macrophage recruitment
- CXCR2/CXCR4
- chemokine receptors, also receptors for MIF
- DAMP
- damage-associated molecular pattern
- DESI
- direct epithelial–stromal interaction
- EGF
- epidermal growth factor
- EGFR
- epidermal growth factor receptor
- EMMPRIN
- extracellular matrix metalloproteinase inducer; synonym of CD147
- ETDRS
- reference visual-acuity scale used in clinical research (Early Treatment Diabetic Retinopathy Study)
- FasL
- Fas ligand, an apoptosis-inducing protein
- FISH
- fluorescence in situ hybridisation
- GAG
- glycosaminoglycan(s)
- GM-CSF
- granulocyte-macrophage colony-stimulating factor
- GVHD
- graft-versus-host disease
- HGF
- hepatocyte growth factor
- HIF-3α
- hypoxia-inducible factor, 3-alpha subunit
- HMGB1
- high mobility group box 1, an alarmin released by injured cells (DAMP)
- IFN-γ
- interferon gamma
- IGF-1
- insulin-like growth factor 1
- IL-1
- interleukin-1
- iNOS
- inducible nitric oxide synthase
- IPAS
- inhibitory PAS domain protein
- KGF
- keratinocyte growth factor
- LASIK
- laser-assisted in situ keratomileusis
- LogMAR
- logarithmic visual-acuity scale
- LOX
- lysyl oxidase, a collagen cross-linking enzyme
- LPS
- bacterial lipopolysaccharide
- M1
- classically activated macrophage, pro-inflammatory profile
- M2
- alternatively activated macrophage, pro-resolving/reparative profile (subtypes M2a-M2d, M2eff)
- MEN2B
- multiple endocrine neoplasia type 2B
- MerTK
- receptor tyrosine kinase involved in efferocytosis
- MIF
- macrophage migration inhibitory factor
- MRI
- magnetic resonance imaging
- NGF
- nerve growth factor
- NK
- neurotrophic keratitis
- NLRP3
- NLRP3 inflammasome (NOD-, LRP- and pyrin domain-containing protein 3)
- NO
- nitric oxide
- NSAID
- nonsteroidal anti-inflammatory drug
- PACAP
- pituitary adenylate cyclase-activating polypeptide
- PAF
- platelet-activating factor
- PAMP
- pathogen-associated molecular pattern
- PDGF
- platelet-derived growth factor
- PED
- persistent epithelial defect
- PEDF
- pigment epithelium-derived factor
- PGE₂
- prostaglandin E2
- PRK
- photorefractive keratectomy (laser surface ablation)
- pro-NGF
- precursor form of NGF
- RGTA
- matrix-therapy ReGeneraTing Agent, e.g. Cacicol
- rhNGF
- recombinant human NGF (cenegermin)
- ROS
- reactive oxygen species
- Smad
- signalling proteins of the TGF-β pathway
- SPK
- superficial punctate keratitis
- sVEGFR-1
- soluble form of VEGF receptor-1 (= sFlt-1)
- sVEGFR-3
- soluble form of VEGF receptor-3
- TGF-β
- transforming growth factor beta
- TIMP
- tissue inhibitor of metalloproteinases
- TLR
- Toll-like receptor
- TNF-α
- tumour necrosis factor alpha
- TRPV4
- transient receptor potential vanilloid 4, a mechanosensitive ion channel
- uPA
- urokinase-type plasminogen activator
- V1
- ophthalmic branch of the trigeminal nerve
- VEGF
- vascular endothelial growth factor
- VEGF-C
- lymphangiogenic isoform of VEGF
- VIP
- vasoactive intestinal peptide
- YAP/TAZ
- Hippo pathway effectors, mechanosensors of matrix stiffness
- α-SMA
- alpha-smooth muscle actin, a myofibroblast marker